Treatment

Treatment and Prevention of Bone Metastases

The management for bone metastases depends largely on the degree of bone damage once the metastases are diagnosed. An initial step in managing bone metastases is often controlling the associated pain, which can be accomplished with pain medications, bisphosphonate drugs, or radiation therapy. Radiation therapy may also be used to kill the cancer cells in the bone in patients whose bones have not already been weakened. If bone metastases have progressed to the point that the bones are unstable or fractured, surgery may be necessary to stabilize them.

Prevention of bone metastases may be possible in some patients who are at high risk of developing bone metastases through treatment with bisphosphonate drugs. Bisphosphonate drugs can effectively prevent loss of bone that occurs from metastatic bone damage, reduce the risk of fractures, and decrease pain.

The following is a general overview of treatment and prevention for bone metastases. Treatment may consist of pain medication, bisphosphonate drugs, radiation therapy, surgery, or a combination of these treatment techniques. In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Circumstances unique to each patient's situation may influence how these general treatment principles are applied. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.

Pain Medications

Since pain is a common complication, and often the initial symptom of bone metastases, management of bone pain is an important step in treatment. Without treatment, bone pain can be debilitating to the point that it compromises a patient's ability to manage normal day-to-day activities.

Cancer-related b one pain can be managed with various pain medications. Despite the claim that 90% of adult cancer patients' pain can be relieved, uncontrolled cancer-related pain is still a concern, particularly for patients who are living at home. Research presented at the 2003 annual meeting of the Oncology Nursing Society indicates that most cancer patients are not prescribed enough medication to control their pain.1

The World Health Organization recommendations for relief of cancer pain indicate that the severity of a patient's pain, rated on a scale of 1-10, will dictate what type of pain medication is used.2

Mild to Moderate Pain (1-3) Non-opioids are the first choice of treatment for mild to moderate pain. This includes medication such as acetaminophen (Tylenol®) or a non-steriodal anti-inflammatory drug (NSAID), such as ibuprofen.

Moderate to Severe Pain (4-6) Patients with moderate to severe pain who have not responded to the first step should receive an opioid. These medications may include codeine, hydrocodone, dilhydrocodiene, oxycodone, propoxyphene, and tramadol. Acetaminophen or a NSAID may be added.

Severe Pain (7-10) Patients with severe pain or patients whose pain has not been relieved by the previous recommendations will usually receive a stronger opioid. Opioids for severe pain may include morphine, oxycodone, hydromorphone, methadone, levophanol, or fentanyl. A non-opioid medication such as aspirin, acetaminophen, or ibuprofen may be added in some cases.

Pain medications may have side effects, including sleepiness, constipation, dizziness, nausea, and vomiting. Relief from pain medications is temporary and the pain may return in a short time; thus, medications are best used at the onset of pain or at regular intervals.

Bisphosphonate Drugs in the Prevention and Treatment of Bone Metastases

Bisphosphonate drugs can effectively prevent loss of bone that occurs from metastatic lesions, reduce the risk of fractures, and decrease pain. Bisphosphonate drugs work by inhibiting bone resorption, or breakdown. Bone is constantly being “remodeled” by two types of cells: osteoclasts, which break down bone; and osteoblasts, which rebuild bone. Although the exact process by which bisphosphonates work is not completely understood, it is thought that bisphosphonates inhibit osteoclasts and induce apoptosis (cell death) in these cells, thereby reducing bone loss. There is also evidence that these drugs bind to bone, thereby blocking osteoclasts from breaking down bone.

Cancer cells release various factors that stimulate osteoclastic activity, causing increased breakdown of bone. By inhibiting osteoclasts, bisphosphonate drugs effectively reduce the detrimental impact that cancer cells have on bone density. An analysis of the results from 30 clinical trials demonstrates that patients with bone metastases treated with a bisphosphonate had a delayed time to skeletal fractures, a reduced need for radiation therapy to treat bone metastasis, a reduction in hypercalcemia (high blood levels of calcium), and a reduction in the need for orthopedic surgery.3

Bisphosphonate drugs that are FDA-approved for the treatment of cancer-related skeletal complications include Zometa® (zoledronic acid) and Aredia® (pamidronate). Of these two drugs, Zometa® appears to demonstrate the strongest activity. An added benefit of Zometa® is that it is administered in a dose ten times lower than Aredia®, which considerably reduces the administration time from several hours to 15 minutes, resulting in a more convenient regimen for patients.

Bisphosphonates have been shown to prevent or delay bone destruction and related pain in clinical trials involving patients with bone metastases related to:

Breast cancer: Bisphosphonate therapy has been shown to prevent or delay bone destruction and related pain in women with breast cancer that has spread to the bone. In a large clinical trial, a total of 751 women with metastatic breast cancer were randomly assigned to receive the bisphosphonate drug, Aredia®, or placebo (inactive substitute). The results showed that 64% of women who received the placebo had significant bone damage, compared with only 51% of those who received the bisphosphonate. The average time to the occurrence of the first bone complication was 13 months in the bisphosphonate group, compared to only 7 months in the placebo group. Furthermore, women who did not receive the bisphosphonate experienced significantly more pain and received more pain medications.4

Prostate cancer: Zometa® has been shown to be a safe and effective treatment in prostate cancer patients with bone metastases. Zometa® significantly reduces the proportion of patients who experience skeletal complications, extends the time to first skeletal complication, and reduces the risk of skeletal complications .5

Zometa® also appears to benefit patients with prostate cancer undergoing androgen deprivation therapy, or “hormonal therapy”. Hormonal therapy in the treatment of prostate cancer has been shown to cause bone loss.6

Researchers from Massachusetts General Hospital and 5 other medical institutions conducted a clinical trial evaluating Zometa® in patients with localized prostate cancer being treated with androgen deprivation therapy. This study included 106 men who were randomly selected to receive either Zometa® or a placebo for one year. Bone mineral density in the spine, hips, and legs increased among patients who were treated with Zometa® and decreased in patients who received placebo.7

Lung cancer: Zometa® is a safe and effective treatment for bone metastases associated with lung cancer. In a clinical trial, 773 patients with lung cancer were randomly assigned to receive Zometa® or placebo via a 15-minute infusion every 3 weeks for 21 months. Results from the two groups were directly compared and showed that the number of patients experiencing at least one skeletal-related event was lower among those who were treated with Zometa® (39%) than patients who received placebo (46%). The patients who received Zometa® went nearly 3 months longer without developing a skeletal-related event and also experienced fewer skeletal-related events.8

Multiple myeloma: A major complication suffered by patients with multiple myeloma is destruction of the bones, causing fractures and pain. A comparison of treatment with chemotherapy plus the bisphosphonate drug Aredia® to chemotherapy alone showed that patients who received the bisphosphonate had fewer bone fractures and decreased pain. In addition, some patients lived longer.9

Research indicates that Zometa® is as effective as Aredia®. Among 1,648 patients with multiple myeloma or advanced breast cancer who had at least one bone lesion, pain and the use of pain medication was decreased with both treatments. However, patients who received Zometa® experienced significantly less need for radiation therapy to treat bone complications.10

Renal cell carcinoma: Researchers from Pennsylvania have reported that Zometa® improves outcomes and reduces skeletal-related events in patients with renal cell carcinoma and associated bone metastases. The researchers analyzed data from 74 patients with renal cell carcinoma who were involved in a larger trial that involved patients with other types of cancers. Patients with renal cell carcinoma may be at a greater risk for developing skeletal-related events than patients with other types of solid cancers. The proportion of patients with renal cell carcinoma was nearly twofold greater than the proportion of patients in the entire population (44% vs. 74%).

The patients were treated with Zometa® or placebo (inactive substitute) and compared for the development of skeletal-related events, which included bone fracture, spinal cord compression, or the need for radiation or surgery for the treatment of bone metastasis.

Patients treated with Zometa® had a 61% reduced risk of developing a skeletal-related event than those who received a placebo. Also, the patients who received Zometa® had less cancer progression in their bones and lived longer.11

Radiation Therapy in the Treatment of Bone Metastases

For metastatic lesions that do not represent an immediate risk of fracture, radiation is effective for reducing bone pain and progression of the cancer. Radiation is especially useful when metastatic lesions are limited to a single area.

One type of radiation therapy is called radiopharmaceutical therapy. This approach involves injecting a radioactive substance, such as strontium-89, into a vein. This substance is attracted to areas of bone that contain cancer. Providing radiation directly to the bone in this way destroys active cancer cells in the bone and can relieve symptoms. Two possible side effects of radiopharmaceutical therapy are decreased blood counts with increased risk of bleeding, and rarely, leukemia.

Surgery in the Treatment of Bone Metastases

When there is an immediate or significant risk of fracture, surgery may be necessary to stabilize the weakened bone. Metal rods, plates, screws, wires, nails, or pins may be surgically inserted to strengthen or provide structure to the bone damaged by metastasis.

Strategies to Improve Treatment and Prevention of Bone Metastases

The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment and prevention of bone metastases will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving the treatment of bone metastases include the following:

Bisphosphonate Drugs
The bisphosphonate drugs Zometa® and Aredia® continue to be evaluated in clinical trials in order to determine their ability to decrease skeletal complications from cancer, reduce osteoporosis, and prevent the spread of cancer in bones. Other bisphosphonate drugs such as clodronate and Boniva ® are also being evaluated in clinical trials. Results from a clinical trial presented at the 2004 annual meeting of the American Society of Clinical Oncology suggest that clodronate may prevent or delay bone metastases from occurring and improve survival for patients with early stage breast cancer.12

The 1,069 patients with early stage breast cancer involved in this study were randomly assigned to receive clodronate or placebo for 2 years. Compared to placebo, clodronate significantly reduced the risk of patients developing bone metastases by 45-50% during the 2 years that medication was administered. Patients continued to experience a significant benefit from the clodronate 5 years after treatment. In addition, patients who received oral clodronate lived more than 2 years longer than patients who received placebo. Clodronate is currently under evaluation by the FDA for approval in the U.S.

New Biological Therapy
In one clinical trial, the biological therapy atrasentan (Xinlay™) slowed progression of prostate cancer, including progression to the bones, and produced a small improvement in quality of life. The results of this study were reported at the 40th annual meeting of the American Society of Clinical Oncology in mid 2004.

Biological therapy involves the administration of naturally occurring substances that increase the body's natural immune defenses or interrupt the unnatural growth patterns of cancer cells. These therapies may be produced in a laboratory to closely resemble the natural substances produced in the body. Atrasentan is a biological therapy that interrupts the activity between a protein located on the outside of the cancer cell, called a receptor, and a molecule circulating in the blood, called endothelin. Under normal conditions, these cellular components stimulate cell growth and survival, hallmark characteristics of cancer cells.

Endothelins are small peptides comprised of 21 amino acids, the building blocks of protein. These molecules occur naturally in the body and are known to be involved in constricting blood vessels, stimulating cell growth, and increasing cell survival. Endothelins cause these processes by binding to receptors located on the outside of some cells, called endothelin receptor A and endothelin receptor B. Atrasentan works by blocking the endothelin receptor A, so that the endothelins cannot bind and increase cell growth and survival.

The recent phase III clinical trial of atrasentan involved 809 patients with metastatic prostate cancer that has become resistant to hormonal therapy.13 Patients received atrasentan or placebo (inactive substitute) and the two groups were compared for clinical and x-ray indications of cancer progression and change from baseline in bio-markers of progression, including prostate specific antigen (PSA), bone alkaline phosphatase (BAP), and total alkaline phosphatase (ALP). Alkaline phosphatase is an enzyme that is involved in bone formation and other processes. Blood levels of alkaline phosphatase are increased in patients with bone metastases.

Atrasentan significantly delayed cancer progression in patients with bone metastases,14 but not in the overall group of patients involved in this trial. Results also suggest that atrasentan appears to delay progression of bone metastases, as it was shown to delay BAP progression. Compared to patients that received placebo, patients treated with atrasentan experienced a twofold longer period (a total of 505 days, 251 days more than placebo) before measures of their BAP increased 50% or more from the low point (nadir).

Researchers determined that treatment with atrasentan provided a small improved quality of life over placebo.15 Quality of life was evaluated using two questionnaires that measure symptoms related to prostate cancer, including pain, fatigue, weight loss, and urinary problems. Higher scores indicate better quality of life and fewer symptoms. The questionnaires were filled out before and after treatment. Scores for the patients treated with placebo dropped more between baseline (initial) measurement and post-treatment, indicating a greater reduction in quality of life and increase in symptoms, compared to those treated with atrasentan. The benefit with atrasentan was most apparent with patients who had cancer that had spread (metastasized) only to bone.